1-Boc-3-iodoindazole

A mixture of 3-iodo-1H-indazole (0.2 g, 0.82 mmol), ditert-butyldicarbonate (0.2 g, 0.92 mmol) and triethylamine (1 mL) were put under ultrasonic irradiation for 10 min. The resulted solution was neutralized using HCl 1M and then extracted with dichloromethane (3 × 30 mL). The combined organic layers were dried with anhydrous sodium sulfate and removal of the solvent under vacuum afforded a pure product as a pale yellow crystals.Yield: 100percent; m.p.: 93–95 °C; IR (KBr) ν (cm−1): 1728 (C=O); 1150 (C-O); 424 (C-I). 1H-NMR (CDCl3) δ(ppm): 8.09 (1H, d, J = 8.5 Hz, H-7); 7.55 (1H, t, J = 7.8 Hz, H-4); 7.46 (1H, d, J = 7.9 Hz, H-6); 7.33 (1H, t, J = 7.6 Hz, H-5); 1.71 (9H, s, CH3). 13C-NMR δ (ppm): 148.35; 139.59; 130.17; 129.98; 124.21; 121.96;114.56; 102.95; 85.48; 28.18; HRMS calculated for C12H13IN2O2: 344.0022, Found: 344.0016.tert-Butyl 3-iodo-5-nitro-1H-indazole-1-carboxylate (2b). Prepared from 3-iodo-5-nitro-1H-indazole (0.2g, 0.69 mmol), di-tert-butyldicarbonate (0.17 g, 0.78 mmol) and triethylamine (1 mL) to give 0.27 g ofa pale yellow solid. Yield: 100percent; m.p.: 144–145 °C; IR (KBr) ν (cm−1): 1744 (C=O); 1528 (NO2tert-Butyl 3-iodo-1H-indazole-1-carboxylate (2a). A mixture of 3-iodo-1H-indazole (0.2 g, 0.82 mmol), di-tert-butyldicarbonate (0.2 g, 0.92 mmol) and triethylamine (1 mL) were put under ultrasonicirradiation for 10 min. The resulted solution was neutralized using HCl 1M and then extractedwith dichloromethane (3 30 mL). The combined organic layers were dried with anhydrous sodiumsulfate and removal of the solvent under vacuum afforded a pure product as a pale yellow crystals.Yield: 100percent; m.p.: 93–95 °C; IR (KBr) (cm1): 1728 (C=O); 1150 (C-O); 424 (C-I). 1H-NMR (CDCl3) (ppm): 8.09 (1H, d, J = 8.5 Hz, H-7); 7.55 (1H, t, J = 7.8 Hz, H-4); 7.46 (1H, d, J = 7.9 Hz, H-6); 7.33 (1H, t, J = 7.6 Hz, H-5); 1.71 (9H, s, CH3). 13C-NMR (ppm): 148.35; 139.59; 130.17; 129.98; 124.21; 121.96;114.56; 102.95; 85.48; 28.18; HRMS calculated for C12H13IN2O2: 344.0022, Found: 344.0016.tert-butyl 3-iodo-1 H-indazole-1-carboxylate[390j To a mixture of 3-iodo-1H-indazole (8 g, 32.7 mmol) and Boc2O (8.6 g, 39.2 mmoi) inMeCN (100 mL) was added NaOH (2.0 g, 49, 1 mmoi) at 25 °C and the mixture was stirred for12 h. The mixture was poured into water (1 50 mL), extracted with EA (50 mL*2), and the combined organic phase was washed with saturated brine (200 mL*2), dried with anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by silica gel chromatography to afford the title compound (11.2 g, 97.5percent) as white solid.3-Iodo-1H-indazole (S1, 5.00 g, 19.5 mmol) was placed in a round-bottom flask and dissolved in tetrahydrofuran (100 mL). 4-Dimethylaminopyridine (0.24 g, 1.9 mmol, 0.1 equiv) was then added, followed by di-tert-butyl dicarbonate (5.4 mL, 24 mmol, 1.2 equiv). Triethylamine (5.4 mL, 39 mmol, 2.0 equiv) was slowly added to the clear, brown solution by syringe. The resulting solution was stirred at room temperature until it was complete as determined by TLC. The reaction was then diluted with water (75 mL) and ethyl acetate (50 mL). After separating the layers, the aqueous phase was extracted with additional ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (100 mL), then shaken over magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude product. This material was purified by column chromatography over silica gel (hexanes/ethyl acetate: 100/0 to 90/10) to give the title compound as an orange solid (6.20 g, 93percent).Example 2.1. Pre ration of tert-butyl 3-iodo-lH-indazole-l-carboxylate [00283] 3-Iodo-lH-indazole (5.00 g, 19.5 mmol) was placed in a round-bottom flask and dissolved in tetrahydrofuran (100 ml). 4-Dimethylaminopyridine (0.24 g, 1.9 mmol, 0.1 equiv) was then added, followed by di-iert-butyl dicarbonate (5.4 ml, 24 mmol, 1.2 equiv). Triethylamine (5.4 ml, 39 mmol, 2.0 equiv) was slowly added to the clear brown solution by syringe. The resulting solution was stirred at room temperature and monitored by TLC until complete. The reaction required approximately 2 hours. Once complete, the reaction was diluted with water (75 ml) and ethyl acetate (50 ml). After separating the layers, the aqueous phase was extracted with additional ethyl acetate (3 x 50 ml). The combined organic layers were washed with brine (100 ml), shaken over magnesium sulfate, filtered, and concentrated under reduced pressure to give a dark red oil (8.40 g). The crude material was purified by column chromatography over silica gel (hexanes/ethyl acetate: 100/0 to 90/10) to give the title compound as an orange solid (6.20 g, 93percent). 1H NMR (300 MHz, CDC1DMAP (16.37mmoI) was added to Intermediate-71(39 mmcl) in acetonitrile (50m1). The reaction mixture was then cooled to 0°C. BOC anhydride (39.9mmol) was added to the cooled reaction mixture. The reaction was carried out at room temperature for 16 hours. Then the reaction mixture was diluted with water (lOOmI) and extracted with ethyl acetate. Theorganic layer was dried over anhydrous Na2SO4 and evaporated to obtain ntermediate-72 (7g, pale yellow sofld).Synthesis of tert-butyl 3-iodo-1H-indazole-1-carboxylate (Intermediate-72) Synthesis of tert-butyl 3-[(l E)-3-ethoxy-3-oxoprop-l -en-i -yI]-1 H-indazole-1 -carboxylate(Intermediate-73):To Triethylamine (3m1), Intermediate-72 (5.8mmol) was added to which methyl acrylate(5.8mmol) was further added. The reaction mixture was purged with argon for 10 minutes.The Pd (II) acetate (0.5mmol) and tri-o-tolyl phosphine (0.5mmol) was added to the reactionmixture. The reaction was carried out for 16 hours at room temperature. Then the reaction mixture was filtered through celite, the filtrate was diluted with ethyl acetate (250m1) and washed with NaHCO3 (5Oml) and brine solution. The organic layer was dried over anhydrous MgSO4, and obtained the crude product by evaporating the organic layer under reducedpressure. The crude product was purified using silica gel column using Hexane and Ethyl acetate as the eluent, to obtain lntermediate-73 (500mg, pale yellow liquid). 1H NMR (300 MHz, DMSO-d6): S 8.24-8.27(d, 1H), 8.13-8.16(d, 1H), 7.85-7.90 (d, 1H), 7.65-7.71(t, 1H), 7.45-7.50(t, 1 H), 6.96-7.02(d, 1 H), 3.80(s, 3H), 1 .67(s, 9H).Synthesis of tert-butyl 3-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-1H-indazole-1-carboxylate (Intermediate-73) To Triethylamine (3 ml), Intermediate-72 (5.8 mmol) was added to which methyl acrylate (5.8 mmol) was further added. The reaction mixture was purged with argon for 10 minutes. The Pd (II) acetate (0.5 mmol) and tri-o-tolyl phosphine (0.5 mmol) was added to the reaction mixture. The reaction was carried out for 16 hours at room temperature. Then the reaction mixture was filtered through celite, the filtrate was diluted with ethyl acetate (250 ml) and washed with NaHCO3 (50 ml) and brine solution. The organic layer was dried over anhydrous MgSO4, and obtained the crude product by evaporating the organic layer under reduced pressure. The crude product was purified using silica gel column using Hexane and Ethyl acetate as the eluent, to obtain Intermediate-73 (500 mg, pale yellow liquid). 1H NMR (300 MHz, DMSO-d6): delta 8.24-8.27 (d, 1H), 8.13-8.16 (d, 1H), 7.85-7.90 (d, 1H), 7.65-7.71 (t, 1H), 7.45-7.50 (t, 1H), 6.96-7.02 (d, 1H), 3.80 (s, 3H), 1.67 (s, 9H).A mixture of 3-iodo-1H-indazole (0.2 g, 0.82 mmol), ditert-butyldicarbonate (0.2 g, 0.92 mmol) and triethylamine (1 mL) were put under ultrasonic irradiation for 10 min. The resulted solution was neutralized using HCl 1M and then extracted with dichloromethane (3 × 30 mL). The combined organic layers were dried with anhydrous sodium sulfate and removal of the solvent under vacuum afforded a pure product as a pale yellow crystals.Yield: 100%; m.p.: 93-95 C; IR (KBr) nu (cm-1): 1728 (C=O); 1150 (C-O); 424 (C-I). 1H-NMR (CDCl3) delta(ppm): 8.09 (1H, d, J = 8.5 Hz, H-7); 7.55 (1H, t, J = 7.8 Hz, H-4); 7.46 (1H, d, J = 7.9 Hz, H-6); 7.33 (1H, t, J = 7.6 Hz, H-5); 1.71 (9H, s, CH3). 13C-NMR delta (ppm): 148.35; 139.59; 130.17; 129.98; 124.21; 121.96;114.56; 102.95; 85.48; 28.18; HRMS calculated for C12H13IN2O2: 344.0022, Found: 344.0016.tert-Butyl 3-iodo-5-nitro-1H-indazole-1-carboxylate (2b). Prepared from 3-iodo-5-nitro-1H-indazole (0.2g, 0.69 mmol), di-tert-butyldicarbonate (0.17 g, 0.78 mmol) and triethylamine (1 mL) to give 0.27 g ofa pale yellow solid. Yield: 100%; m.p.: 144-145 C; IR (KBr) nu (cm-1): 1744 (C=O); 1528 (NO2tert-Butyl 3-iodo-1H-indazole-1-carboxylate (2a). A mixture of 3-iodo-1H-indazole (0.2 g, 0.82 mmol), di-tert-butyldicarbonate (0.2 g, 0.92 mmol) and triethylamine (1 mL) were put under ultrasonicirradiation for 10 min. The resulted solution was neutralized using HCl 1M and then extractedwith dichloromethane (3 30 mL). The combined organic layers were dried with anhydrous sodiumsulfate and removal of the solvent under vacuum afforded a pure product as a pale yellow crystals.Yield: 100%; m.p.: 93-95 C; IR (KBr) (cm1): 1728 (C=O); 1150 (C-O); 424 (C-I). 1H-NMR (CDCl3) (ppm): 8.09 (1H, d, J = 8.5 Hz, H-7); 7.55 (1H, t, J = 7.8 Hz, H-4); 7.46 (1H, d, J = 7.9 Hz, H-6); 7.33 (1H, t, J = 7.6 Hz, H-5); 1.71 (9H, s, CH3). 13C-NMR (ppm): 148.35; 139.59; 130.17; 129.98; 124.21; 121.96;114.56; 102.95; 85.48; 28.18; HRMS calculated for C12H13IN2O2: 344.0022, Found: 344.0016.tert-butyl 3-iodo-1 H-indazole-1-carboxylate[00447] To a mixture of 3-iodo-1H-indazole (8 g, 32.7 mmol) and Boc2O (8.6 g, 39.2mmol) in MeCN (100 mL) was added NaOH (2.0 g, 49.1 mmol) at 25 C and the mixture was stirred for 12 h. The mixture was poured into water (150 mL), extracted with EA (50 mLx2), andthe combined organic phase was washed with saturated brine (200 mLx2), dried with anhydrousNa2S04 and concentrated under vacuum. The residue was purified by silica gel chromatographyto afford the title compound (11.2 g, 97.5%) as a white solid. MS (m/z): 477.2 [M+1]+.[390j To a mixture of 3-iodo-1H-indazole (8 g, 32.7 mmol) and Boc2O (8.6 g, 39.2 mmoi) inMeCN (100 mL) was added NaOH (2.0 g, 49, 1 mmoi) at 25 C and the mixture was stirred for12 h. The mixture was poured into water (1 50 mL), extracted with EA (50 mL*2), and the combined organic phase was washed with saturated brine (200 mL*2), dried with anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by silica gel chromatography to afford the title compound (11.2 g, 97.5%) as white solid.3-Iodo-1H-indazole (S1, 5.00 g, 19.5 mmol) was placed in a round-bottom flask and dissolved in tetrahydrofuran (100 mL). 4-Dimethylaminopyridine (0.24 g, 1.9 mmol, 0.1 equiv) was then added, followed by di-tert-butyl dicarbonate (5.4 mL, 24 mmol, 1.2 equiv). Triethylamine (5.4 mL, 39 mmol, 2.0 equiv) was slowly added to the clear, brown solution by syringe. The resulting solution was stirred at room temperature until it was complete as determined by TLC. The reaction was then diluted with water (75 mL) and ethyl acetate (50 mL). After separating the layers, the aqueous phase was extracted with additional ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (100 mL), then shaken over magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude product. This material was purified by column chromatography over silica gel (hexanes/ethyl acetate: 100/0 to 90/10) to give the title compound as an orange solid (6.20 g, 93%).Example 2.1. Pre ration of tert-butyl 3-iodo-lH-indazole-l-carboxylate [00283] 3-Iodo-lH-indazole (5.00 g, 19.5 mmol) was placed in a round-bottom flask and dissolved in tetrahydrofuran (100 ml). 4-Dimethylaminopyridine (0.24 g, 1.9 mmol, 0.1 equiv) was then added, followed by di-iert-butyl dicarbonate (5.4 ml, 24 mmol, 1.2 equiv). Triethylamine (5.4 ml, 39 mmol, 2.0 equiv) was slowly added to the clear brown solution by syringe. The resulting solution was stirred at room temperature and monitored by TLC until complete. The reaction required approximately 2 hours. Once complete, the reaction was diluted with water (75 ml) and ethyl acetate (50 ml). After separating the layers, the aqueous phase was extracted with additional ethyl acetate (3 x 50 ml). The combined organic layers were washed with brine (100 ml), shaken over magnesium sulfate, filtered, and concentrated under reduced pressure to give a dark red oil (8.40 g). The crude material was purified by column chromatography over silica gel (hexanes/ethyl acetate: 100/0 to 90/10) to give the title compound as an orange solid (6.20 g, 93%). 1H NMR (300 MHz, CDC13): delta 8.12 (d, J = 8.4 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 1.73 (s, 9H); 13C NMR (75 MHz, CDC13): delta 148.3, 139.6, 130.2, 129.9, 124.1, 121.9, 114.5, 102.8, 85.4, 28.1; ESI-MS (M-C4H9): m/z 288.To a stirred solution of indazole 16 (1.2 g, 10 mmol) in DMF(10 mL) was added potassium carbonate (1.0 g, 20 mmol) andiodine (3.0 g, 12 mmol). The mixture was then stirred at roomtemperature overnight. Next, the reaction mixture was poured into100 mL aq. NaHSO3 (10%) and extracted three times with ethylacetate. The organic layer was washed with brine and dried overanhydrous sodium sulfate. The solvent was evaporated underreduced pressure to give a crude product which was immediatelydissolved in dioxane (20 mL) followed by the addition of Et3N(3.0 mL, 22 mmol), (Boc)2O (2.5 mL, 11 mmol) and DMAP (0.0012 g, 0.1 mmol). The reaction mixture was stirred at room temperature for 1 h, and then diluted with saturated NaHCO3 (aq) and extractedwith ethyl acetate. The organic layer was washed with brine anddried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure and the residue was purified by flash columnchromatography (hexane/ethyl acetate = 10/1) to yield 17a asa yellow solid (2.8 g, 82%). 1H NMR (400 MHz, CDCl3) delta 8.12 (d, J = 8.5 Hz, 1H), 7.60-7.56 (m, 1H), 7.49 (dt, J = 8.0, 1.1 Hz, 1H), 7.39-7.35 (m, 1H), 1.72 (s, 9H). 13C NMR (101 MHz, CDCl3) delta 148.36, 139.62, 130.19, 129.96, 124.18, 121.97, 114.56, 102.89, 85.49, 28.15.HRMS (ESI) m/z calcd. for C12H14IN2O2 [M+H]+ 345.0094, found345.0092.Reference DMAP (16.37mmoI) was added to Intermediate-71(39 mmcl) in acetonitrile (50m1). The reaction mixture was then cooled to 0C. BOC anhydride (39.9mmol) was added to the cooled reaction mixture. The reaction was carried out at room temperature for 16 hours. Then the reaction mixture was diluted with water (lOOmI) and extracted with ethyl acetate. Theorganic layer was dried over anhydrous Na2SO4 and evaporated to obtain ntermediate-72 (7g, pale yellow sofld).Synthesis of A mixture of 15 (0.560 g, 1.28 mmol), 17a (0.400 g, 1.06 mmol), cesium carbonate (1.68 g, 5.12 mmol) and [1, 10-bis(diphenylphosphino)ferrocene]palladium (II) dichloride (0.026 mg, 0.032 mmol)in dioxane (8.0 mL) and H2O (2.0 mL) was purged with argon. Thereactionwas then sealed and heated with stirring under microwaveirradiation at 100 C for 20 min. Next, the reaction mixture wasquenched with water and extracted with ethyl acetate. The organiclayer was washed with brine and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure andthe residue was purified by flash column chromatography (hexane/ethyl acetate 4/1) to yield 18a as a yellow solid (0.35 g, 55%). 1HNMR (500 MHz, CDCl3) delta 7.93 (d, J = 8.3 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.32-7.21 (m, 3H), 7.14 (ddd, J = 7.9, 6.0, 1.7 Hz, 1H), 7.02 (s, 1H), 6.75 (d, J = 7.9 Hz, 1H), 1.37-1.31 (m, 3H), 1.11 (d, J = 7.6 Hz, 18H), 1.06 (s, 9H). 13C NMR (126 MHz, CDCl3) delta 150.03, 149.28, 140.61, 139.23, 129.57, 126.92, 125.65, 123.30, 122.25, 121.12, 120.75, 111.57, 110.04, 109.55, 108.70, 83.34, 27.23, 18.03, 12.88. HRMS (ESI) m/zcalcd. for C29H40N3O3Si [M+H]+ 506.2833, found 506.2831.

Molecular Weight:344.15
XLogP3:3.5
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:344.00218
Monoisotopic Mass:344.00218
Topological Polar Surface Area:44.1
Heavy Atom Count:17
Complexity:303
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes